A98-09 Evaluation of Sex Differences in Pulmonary Mycobacterium Avium Complex Disease Using a Murine Model of Pulmonary Mycobacterium Avium Infection

Abstract Rationale The incidence and prevalence of pulmonary nontuberculous mycobacterial (NTM) disease has been increasing. However, it remains a refractory infectious disease with no definitive curative treatment, and the host factors contributing to its onset and progression have not yet been fully elucidated. Clinically, male sex is recognized as an independent risk factor for poor prognosis in pulmonary NTM disease, but the underlying mechanisms remain poorly understood. Among the causative species, the Mycobacterium avium complex (MAC) is the most common pathogen. This study aimed to evaluate the influence of sex differences on disease phenotype and host immune responses using a murine model of pulmonary M. avium infection. Methods Eight-week-old male and female BALB/c mice were infected with M. avium (1 × 107 CFU) intranasally. Lung pathology, lung bacterial loads, and total immune cell counts and differential cell fractions in bronchoalveolar lavage fluid (BALF) were examined at 2 months and 4 months after M. avium infection. In addition, comprehensive transcriptome analysis in the infected lungs and uninfected control lungs was performed by RNA-seq at 2 months after M. avium infection. Results No differences were observed in the lung histopathology between male and female mice at 2 and 4 months after infection. Male mice exhibited significantly higher lung bacterial loads than female mice at both 2 months (p = 0.0333) and 4 months (p = 0.0119) after M. avium infection. However, no significant differences in total immune cell counts or differential cell fractions in BALF were observed between sexes. RNA-Seq analysis of uninfected control lungs identified 699 upregulated and 250 downregulated genes in male mice compared with female mice (FDR < 0.05). Two months after M. avium infection, 92 genes were upregulated and 68 genes were downregulated in the lungs of infected male mice compared with those of female mice (FDR < 0.05). Conclusions In a murine model of pulmonary M. avium infection, male mice exhibited higher lung bacterial loads than female mice, despite no significant differences in lung pathology, total immune cell counts, and differential cell fractions in BALF. These results suggest that this difference may be attributed more to qualitative rather than quantitative differences in immune responses. Transcriptomic profiling revealed distinct gene expression patterns between sexes, which may reflect underlying biological variations in the host response. These findings provide a foundation for further studies exploring sex-related factors that influence susceptibility and disease progression in pulmonary MAC disease. This abstract is funded by: Kakenhi